Athletic patch

ABSTRACT

The present invention relates to patches for the administration of an athletic supplement to subjects engaged in rigorous exercise or heavy outdoor work. The invention also relates to methods of administering nutrients to subjects using the patch of the invention.

RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.11/119,538, filed Apr. 29, 2005, which is a continuation of U.S.application Ser. No. 10/271,827, filed on Oct. 15, 2002, entitled“Athletic Patch” and now U.S. Pat. No. 6,893,656, which is acontinuation of U.S. application Ser. No. 09/452,517, filed Dec. 1,1999, entitled “Athletic Patch” and now U.S. Pat. No. 6,45,514, whichclaims priority under 35 USC §119 to U.S. Provisional Application Ser.No. 60/110,771 filed Dec. 3, 1998, and entitled “Athletic Patch”.

FIELD OF THE INVENTION

The present invention relates to patches for the administration of anathletic supplement to subjects engaged in rigorous exercise or heavyoutdoor work. The invention also relates to methods of administeringnutrients to subjects using the patch of the invention.

BACKGROUND OF THE INVENTION

Strenuous exercise that occurs during athletic events, such asmarathons, causes trauma to the body. For instance, exercise causes therelease of adrenocorticotropin (ACTH) which leads to the increasedproduction and release of cortisol. High levels of cortisol cause therelease of amino acids from muscle tissue and prevent absorption ofglucose, causing the catabolic breakdown of muscle tissue. Many cortisolblockers can be used to prevent the catabolic breakdown of muscletissue, including leucine, antioxidants, and glutamic acid.

Exercise also causes the loss of many nutrients. Many types of sportsdrinks have been developed and marketed with the intent to replace thenutrients lost during athletic events. These sports drinks, such asGatorade utilize sugar and electrolytes with water to prevent loss ofcarbohydrates and water during exercise. In general these drinks includesugars, electrolytes, vitamins, minerals, amino acids, and otherimportant nutrients. In some cases pyruvate has also been added to suchdrinks to improve performance and help to prevent the detrimentalbreakdown of protein as an energy source.

There are several types of sports drinks currently available. One typeincludes sugar and water, such as the drink marketed by Coca-ColaCompany under the trade name “Max”. Max contains a 5% solution ofdextrose and maltodextrin. Other types of sports drinks include sugar,water and electrolytes, and in some cases vitamins. These types ofdrinks include Gatorade and Exceed. Gatorade, for instance, contains a6% solution of sucrose and glucose, 220 mg of sodium and 50 mg ofpotassium per serving and some vitamin C. Even other drinks, such asBody Fuel 450, include sugar, water, electrolytes, vitamins andminerals. The most comprehensive of these drinks include the followingingredients:

1-100 g of at least 1 carbohydrate,

2-2500 mg of at least 1 electrolyte,

0.1-750 mg of at least 1 ammonia neutralizer,

at least one energy enhancer, preferably selected 2000 mg vitamins ofthe vitamin B group, 10-40,000 mg L-carnitin, creatine and choline, and1-100 mg branched chain amino acids,

at least one antioxidant, preferably selected from β-carotene in aquantity of 2 μg-200 μg, vitamin C in a quantity of 10-250 mg, vitamin Ein a quantity of 8-30 I. selenium in a quantity of 10-300 μg,

1-30 mg of at least 1 membrane stabilizer,

1-200 μg of at least 1 neuromuscular enhancer, and

water in a quantity at least sufficient to provide a solution such thateach of the above components are substantially dissolved and which isready for consumption by drinking.

One problem with all of these drinks is that they are dependent upongastrointestinal absorption in order for the nutrients to beadministered and disseminated among the body. Under conditions ofdehydration and electrolyte imbalance, normal absorption may not occur.Additionally, not all of the nutrients are metabolized at the same rate,and thus may not be effectively used during the period of the athleticevent.

Much research has indicated that amino acids of the branched chain typeincluding valine, leucine and isoleucine, are essential to maintainingand repairing cellular integrity during athletic stress. One problemwith these amino acids, however, is their adverse palatability, makingit difficult to incorporate them into sports drinks.

Additionally, the sports drinks require that energy be utilized todigest and process the nutrients therein. This process requires the useof energy which could otherwise be used to fuel the muscles and provideenergy to the athlete.

SUMMARY OF THE INVENTION

The present invention relates to methods and products for replenishingnutrients and supplying additional components to a subject involved instrenuous exercise which avoids many of the limitations associated withsports drinks.

The invention in one aspect is a patch for administering nutrientsutilized during exercise and other periods of high energy consumption.The patch is particularly useful for athletes during sporting eventssuch as marathons in which the nutrients are used rapidly by the body.The nutrients are delivered from the patch directly to the blood streamwhere they can supply the necessary energy or maintenance of homeostaticconditions in the body. There is no need for the nutrients to passthrough the gastrointestinal tract where absorption would be a limitingfactor.

In one aspect the invention is an article of manufacture including apatch for topical delivery of an athletic supplement to a subject whichincludes at least two compounds selected from the group consisting of acarbohydrate, an electrolyte, a vitamin, an amino acid, chromium, and amineral. Preferably the patch includes at least three of thesecompounds. Preferably the athletic supplement includes at least onecarbohydrate.

In one embodiment the athletic supplement includes an electrolyte. Inanother embodiment the athletic supplement includes a vitamin. Inanother embodiment the athletic supplement includes an amino acid. Inyet another embodiment the athletic supplement includes chromium.According to another embodiment the athletic supplement includes anenergy enhancer. Preferably, the athletic supplement includes a vitamin,an amino acid, chromium, and an energy enhancer.

The patch may include many different concentrations of the components ofthe athletic supplement. In a preferred embodiment the athleticsupplement is at least 1 to 100 grams of carbohydrate and 2 to 2500milligrams of electrolyte.

In addition to the above-described components, the athletic supplementmay also include at least one of the following compounds: sodiumchloride, potassium chloride, anhydrous magnesium sulphate,dodecahydrated disodium hydrogen phosphate, hydrated sodium dihydrogenphosphate, dextrose, sucrose, ascorbic acid, pyridoxine hydrochloride,sodium citrate, and citric acid.

The patch may be any type of conventional patch, such as a transdermalpatch, a sublingual patch, or a buccal patch. Preferably, the patch is atransdermal patch for administering the athletic supplement to skin ofthe subject. In a preferred embodiment the patch includes a permeationenhancing amount of at least one skin permeation enhancer. Preferablythe skin permeation enhancer is selected from the group consisting ofmenthol, eucalyptol, glyceryl monostearate and d-limonene. In anotherpreferred embodiment the patch is a sublingual patch.

According to another aspect of the invention an article of manufactureis provided. The article of manufacture includes a patch for topicallyadministering an athletic supplement to a subject, wherein the device isformulated to deliver the athletic supplement within 24 hours. In oneembodiment the patch is a transdermal patch for administering theathletic supplement to skin of the subject.

The patch may be designed to release the athletic supplement over anyperiod of time within 24 hours. In one embodiment the patch isformulated for administering the athletic supplement within 12 hours. Inanother embodiment, the patch is formulated for administering theathletic supplement within 6 hours. In yet another embodiment the patchis formulated for administering the athletic supplement within 4 hours.

According to another embodiment the patch includes a permeationenhancing amount of at least one skin permeation enhancer selected fromthe group consisting of menthol, eucalyptol, glyceryl monostearate andd-limonene.

Preferably the athletic supplement includes at least one carbohydrate.

In one embodiment the athletic supplement includes an electrolyte. Inanother embodiment the athletic supplement includes a vitamin. Inanother embodiment the athletic supplement includes an amino acid. Inyet another embodiment the athletic supplement includes chromium.According to another embodiment the athletic supplement includes anenergy enhancer. Preferably, the athletic supplement includes a vitamin,an amino acid, chromium, and an energy enhancer.

According to yet another aspect the invention is a method ofadministering nutrients to a subject. The method includes the step oftransdermally administering an athletic supplement to a subject whilethe subject is undergoing a physical activity to provide the subjectwith nutrition and energy required to perform the physical activity.Preferably, the athletic supplement is administered using the patch ofthe invention described above.

Preferably the athletic supplement includes at least one carbohydrate.

In one embodiment the athletic supplement includes an electrolyte. Inanother embodiment the athletic supplement includes a vitamin. Inanother embodiment the athletic supplement includes an amino acid. Inyet another embodiment the athletic supplement includes chromium.According to another embodiment the athletic supplement includes anenergy enhancer. Preferably, the athletic supplement includes a vitamin,an amino acid, a mineral, and an energy enhancer.

In another aspect, the invention is article of manufacture which is apatch for topical delivery of an athletic supplement to a subject whichincludes at least an amino acid, chromium, and a vitamin. Preferably thevitamin is vitamin B-15. In one embodiment, the patch is a transdermalpatch.

Each of the limitations of the invention can encompass variousembodiments of the invention. It is, therefore, anticipated that each ofthe limitations of the invention involving any one element orcombinations of elements can be included in each aspect of theinvention.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 depicts a transdermal patch having a diffusion layer matrix.

FIG. 2 shows a multi-compartmentalized transdermal patch.

DETAILED DESCRIPTION OF THE INVENTION

The invention relates to methods and products for delivering nutrientsto a subject involved in rigorous exercise. In one aspect the inventionis a delivery system for the delivery of nutrients through the skin ormucosal membrane of a subject during a defined period of time duringwhich the subject is involved in a physical activity and which includesat least two compounds selected from the following compounds: acarbohydrate, a vitamin, an amino acid, chromium, a mineral, and anelectrolyte.

The delivery of an athletic supplement using a patch offers severaladvantages over traditional delivery methods. For instance, the patchavoids gastrointestinal metabolism of the athletic supplement, reducesfirst pass effects and may if desirable provide a longer course ofrelease of the components of the athletic supplement than traditionalmethods such as the use of sports drinks

During strenuous exercise, the ability of the body to dissipatemetabolically produced heat depends on the subject's ability to form andvaporize sweat. There is a progressive increase in body temperature asthe ability to sweat decreases. In addition to the increased bodytemperature and perspiration, exercise also causes an increase in pulserate, a decrease in the blood volume and biochemical changes associatedwith the metabolism of compounds to produce energy, such as glucoseutilization. During extreme exercise, carbohydrates are increasinglyused as the source of readily available energy, as opposed to fatmetabolism. The body will continue to utilize carbohydrates as the majorsource of energy during the prolonged periods of exercise. If thissupply of carbohydrates, however, is depleted, the body begins toutilize proteins to generate energy. The amino acid utilizationresulting from protein results in a depletion of essential amino acidsin the plasma which can cause many detrimental effects, such as the lossof the ability to repair damaged tissue.

A desirable nutritional supplement would be one which causes themaintenance of blood volume and cardiac output, provides a readilyavailable energy source, improves skin blood flow, increases the numberof electrolytes, reduces breakdown of proteins, and decreases the timeneeded for repair of the body following strenuous exercise.

The patch of the invention is one which provides an athletic supplementto a subject. The athletic supplement prevents the adverse effects ofphysical exertion or environmental exposure. An athletic supplement that“prevents the adverse effects of physical exertion or environmentalexposure” as used herein is one which achieves one or more of thefollowing parameters: maintains carbohydrate levels in blood within thenormal range, prevents loss of electrolytes below a normal range, orprovides an energy enhancing amount of an energy enhancer in the plasma.A normal range of carbohydrates in the blood as used herein is thatamount which during periods of extreme exercise is sufficient to preventprotein metabolism. That amount is within the range of 65-140 mg/dl.Preferably the amount is within the range of 80-120 mg/dl.

In one aspect the invention is a patch for topical delivery of anathletic supplement to a subject which includes at least two compoundsselected from the group consisting of a carbohydrate, an electrolyte, avitamin, an amino acid, a mineral, and an energy enhancer. The patch mayalso include other nutrients such as sodium chloride, potassiumchloride, anhydrous magnesium sulphate, dodecahydrated disodium hydrogenphosphate, hydrated sodium dihydrogen phosphate, dextrose, sucrose,ascorbic acid, pyridoxine hydrochloride, sodium citrate, and citricacid.

The carbohydrate used in the patch may be a simple saccharide, a complexsaccharide or a mixture thereof. Simple saccharides generally providethe most immediate energy source for the athlete. It is desirable,however, to include a mixture of carbohydrates to provide sustainedenergy source and to avoid fluctuations in serum glucose levels whichoccur as the result of ingestion of glucose. Complex saccharides arecarbohydrate polymers which generally are approximately 5-10 monomericunits. These compounds are commercially available. The polymers areconverted into simple carbohydrates in vivo by digestion, hydrolysis andhost catabolic pathways. Dextrins, for example, are glucose polymerswhich are generally obtained by hydrolysis of starch and are availablecommercially from numerous sources.

Carbohydrates include sugars, monosaccharides, oligosaccharides, such asfor example, N-acetyl-D-galactosamine, D-glucose (dextrose, corn sugar),D-glucosamine, N-acetyl-D-glucosamine, N-methyl-D-glucosamine,D-mannose, D-ribose, D-xylose, D-fructose, D-galactose, D-galactosamine,cellobiose, maltose, galactose, and sucrose. The carbohydrates may be inthe form of monomers or polymers, e.g., glucose polymers, such asmaltose or maltodextrin. The carbohydrate polymers are the preferredsource of carbohydrate because they can be cleaved enzymatically in thebody to supply a constant source of energy over a course of severalhours.

The preferred amount of carbohydrates within the patch will varydepending on many factors such as the size of the patch and the type ofactivity that the patch will be used for. The actual amount ofcarbohydrates may range from 50 mg-100 g. A more preferred range is from1-5 g.

The patch may also include electrolytes. Electrolytes in the appropriatequantities increase the efficiency of the body to utilize glycogen andimprove muscle activities. Potassium is an extremely important source ofelectrolyte that is involved in sugar absorption in the gastrointestinaltract. Potassium deficiency is very common in athletes. The appropriatesupplementation reduces physical and metabolic stress and improvesperformance. The best source of potassium is potassium chloride. It hasbeen found that a significant amount of sodium is lost in sweat duringprolonged exercise. If the sodium that is lost is not replenished, thereis a contraction of plasma volume, a suppression of the thirstmechanism, and a loss in ability of distal renal tubules to resorbwater.

Electrolytes are salts of a metal of the group I and II of the periodicsystem. Electrolytes include, for example, inorganic and organic saltsof sodium, potassium, calcium and/or magnesium. Examples of these saltsinclude sodium acetate, acidic sodium citrate, acidic sodium phosphate,sodium amino salicylate, sodium bicarbonate, sodium bromide, sodiumchloride, sodium citrate, sodium lactate, sodium phosphate, sodiumsalicylate, sodium sulphate (anhydrous or Glauber's salt), potassiumacetate, potassium bicarbonate, potassium bromide, potassium chloride,potassium citrate, potassium-D-gluconate, mono- and dibasic potassiumphosphate, calcium acetate, calcium chloride, calcium citrate,calcium-D-gluconate, calcium lactate, calcium laevulinate, dibasiccalcium phosphate, magnesium chloride and magnesium sulphate. Preferredelectrolytes include sodium bicarbonate, sodium phosphate, potassiumbicarbonate, potassium chloride, dibasic potassium phosphate, calciumcarbonate and magnesium carbonate.

The actual amount of electrolytes present in the patch will varydepending on many factors described herein. In general, the electrolytesare present in the patch in amounts of 2-2500 mg and preferably inamounts of 5-1000 mg.

Vitamins may also be included in the patch. Vitamins are organiccompounds required for the transformation of energy for regulation ofthe metabolism of structural units. Vitamins include, for example,vitamin A, vitamin D3, vitamin Z, vitamin E, folic acid, thiamine,riboflavin, niacin, vitamin B6, vitamin B12, biotin, pantothenic acid,and vitamin K1. Some of the vitamins included in the patch also functionas antioxidants. These include, for example, β-carotene, vitamin C,vitamin E and selenium.

A particularly preferred type of vitamin which can be included in thepatch is vitamin B-15. Vitamin B-15, also known as Russian B-15 ordimethylglycine (DMG), has been linked to the improved performance ofmany Soviet athletes. The physiological effects of vitamin B-15 arediverse and include at least the following: the ability to increaseoxygen utilization by muscle, depress muscle glycolysis, spare glycogenand thus enhance endurance, prevent exercise-induced hypoglycemicfatigue by normalizing blood glucose during exercise, lower bloodlactate during exercise (increased blood lactate has been associatedwith the onset of fatigue), activate lipid metabolism, and increase worktolerance). It is believed that DMG functions as a methyl donor bytransferring methyl groups to compounds such as folic acid which causethe biosynthesis of important molecules.

The patch also includes amino acids or salts thereof. Muscle cellsrequire both essential and nonessential amino acids to undergo proteinsynthesis. It is known that the branched amino acids, and leucine inparticular, stimulate protein synthesis in at least some skeletalmuscles and the liver. Skeletal muscle is the primary site for theinitial step in the catabolism of branched amino acids, which isreferred to as the oxidation resulting in energy production. The firststep in the oxidative catabolism of branched amino acids istransamination, which is the enzymatic transfer of the α-amino group toanother molecule. Transamination produces a branched ketoacid. Thebranched ketoacid formed by transamination can either accept an aminogroup to become a branched amino acid or can be irreversibly catabolizedfor calories. Strenuous exercise increases the oxidation of branchedamino acids. During exercise, the branched amino acids are predominantlyderived from muscle protein, causing increased amounts of proteindegradation. The branched amino acids, in addition to providing energy,also remove lactate from muscle. In preferred embodiments the patchincludes at least one branched amino acid. It is especially preferredfor the patch to include amino acids when the patch is administered atthe end of the exercise or after the exercise is complete. Theadministration of amino acids after exercise increases protein synthesisand reduces protein breakdown, thus improving net muscle proteinbalance. Acta. Physiol. Scand., V. 162, p. 377-387 (1988).

Essential amino acids include isoleucine, leucine, valine, lysine,methionine, phenylalanine, threonine, and tryptophan. The nonessentialamino acids include alanine, arginine, aspartic acid, glutamic acid,aminoacetic acid, histidine, proline, serine, tyrosine, and cysteine.

The actual amount of amino acid included in the patch will varydepending on the type of amino acid and other parameters discussedherein. Preferably the amino acids are present in a range of 5-250 mg.

Chromium may also be included in the patch. Chromium is a component ofglucose tolerance factor (GTF) which potentiates the action of insulin.Chromium has been shown to increase lean muscle deposition in humanswhen administered as a supplement and also to increase glucose toleranceand insulin sensitivity. (Anderson, R. A., Eur. J. Appl. Physiol., V.63, p. 146 (1991)). When chromium is administered during exercise, it isbelieved to facilitate the interaction between insulin and insulinreceptors on tissues such as muscle and fat. Thus, it is desirable toinclude chromium in the patch.

It is desirable in some embodiments to include pyruvate in the patch inorder to enhance the energy stores available to cells. Even a smallamount of pyruvate improves performance and endurance during athleticevents because it enhances entrance of acetyl CoA into the Krebs cycle.The Krebs cycle, a biochemical pathway, provides a working muscle withenergy source. Under normal conditions pyruvate is formed from glucose,but during periods of exercise not enough pyruvate can be generated fromthis source to supply the cells with energy. A loss of pyruvate alsoprevents metabolism of fats as an energy source because fats enter theKrebs cycle as acetyl CoA. Thus, as pyruvate concentration is decreasedin the bloodstream, a loss of pyruvate as a direct energy source as wellas the ability to utilize fat as an energy source is lost. Thus, bysupplementing the blood with pyruvate, adequate energy supplies can beachieved.

During the period of exercise and recovery after exercise, thefast-twitch muscles produce lactic acid, which is then available for afuel for slow-twitch, highly oxidative skeletal muscle fibers. Thus,lactic acid provides a more immediate fuel source than dietary glucose.Lactic acid is not a desirable fuel source for the body. U.S. Pat. No.5,420,107, issued to Brooks, discloses a series of lactic acid-likesubstances which provide an immediate fuel source to athletes duringexercise and recovery from exercise which augment the beneficial effectsof dietary glucose and other carbohydrates. The patent teaches that atleast one organic lactic acid salt in an amount sufficient to affect anmammal's fluid electrolyte or carbohydrate balance during exerciseand/or subsequent recovery can be administered as a nutritionalsupplement. Such a supplement may also be added to the patch of theinstant invention.

Although it is desirable to maintain concentrations of pyruvate withinnormal ranges, an excess of pyruvate should not be added. Lactate isderived directly from pyruvate during strenuous exercise which occurs inan anaerobic manner Build up of lactate in the muscle can cause musclefatigue.

The patch may also include a mineral. Minerals include but are notlimited to trace elements, iron, magnesium, copper, zinc, manganese,selenium, molybedemum, chromium, and iodide.

The patch also may include ammonia neutralizers, which in general areamino acids, e.g., αx-alanine, arginine, asparagine, cystine, cysteine,aspartic acid, glutamic acid, glutamine, glycine, histidine,α-hydroxylysine, hydroxyproline, lysine, 3-monoiodotyrosine, leucine,methionine, norleucine, phenylalanine, proline, threonine, serine,tyrosine, tryptophan and the salts thereof, e.g., potassium, magnesium,and the phosphate salts.

The patch may also include energy enhancers. As used herein an “energyenhancer” is a compound which stimulates muscular activity. Energyenhancers include, for example, vitamins of the vitamin B group,creatine, choline, and some branched chain amino acids. Vitamins of thevitamin B group include, for example, vitamin B1 (thiamine, aneurin),vitamin B2 (riboflavin), vitamin PP (niacinamide), vitamin B6(pyridoxine), pantothenic acid, and L-carnitine. Choline includechloride and other forms of choline. Useful branched chain amino acidsinclude, for example, leucine, valine, and isoleucine. Preferredquantities of vitamins of the vitamin B group are 10-500 μg. Preferredquantities of branched chain amino acids are 3-10 mg. Preferredquantities of the others are 500 mg. A preferred energy enhancer is aneuromuscular enhancer. Neuromuscular enhancers include, for example,choline (choline chloride), and higher saturated fatty alcohols,particularly C₂₅-C₃₀ fatty alcohols (e.g., octacosanol or cerotylalcohol). Neuromuscular enhancers may be present in amounts of 1-2000μg, or more preferably 3-20 μg and most preferably about 5 μg.

It is possible to include many of the components of the athleticsupplement in multiple patches. For instance, one patch may contain thecarbohydrate and another patch may contain a group of other compoundssuch as vitamins, amino acids, electrolytes, minerals, and energyenhancers. The use of multiple patches is advantageous for example whenit is desirable to administer a large amount of some components, such ascarbohydrates and smaller amounts of other components.

The amount of nutrients within the athletic supplement will varydepending on many factors. For instance, the amount and type ofnutrients included in a particular athletic supplement will depend onthe nature and duration of the exercise being performed by the subject,the size and weight of the subject, and whether the subject is usingsupplemental sources of nutrients, such as sports drinks One goal of thepatch of the invention is to administer nutrients such that homeostaticconditions are maintained during the athletic event. Therefore, it isdesirable to administer nutrients in an amount which will replace thosebeing depleted by the athletic event. Normal levels of various nutrientsthat are present in a subject in the resting state are well known in theart and are extensively described in Remington: The Science and Practiceof Pharmacy, Alfonso R. Jennaro, Ed., 19th Ed., 1995, Mack PublishingCompany, Easton, Pa. Many of the nutrients incorporated in the athleticsupplement are described in chapter 65, entitled Vitamins and OtherNutrients, of Remington. Other nutrients are described in otherchapters. Based on this disclosure as well as many other references,those of ordinary skill in the art would be able to determine the actualamount of particular nutrients which should be included in the patch ofthe invention in order to replace depleted nutrients during periods ofexercise.

In one embodiment the patch includes the following components in thefollowing amounts sodium chloride: 69.6 mg; potassium chloride: 288.0mg; magnesium sulphate: 148.0 mg; sodium citrate: 120.0 mg; disodiumhydrogen phosphate: 480.0 mg; sodium dihydrogen phosphate: 111.6 mg;ascorbic acid: 100.0 mg; pyridoxine hydrochloride: 25.0 mg; citric acid:420.0 mg; sucrose: 2 gm; dextrose:2 gm.

The patch replaces nutrients which are lost during physical exertion. Itis particularly useful for a subject requiring sustained energy, such asan athlete, or a subject who undergoes physical exertion at work. A“subject” as used herein includes any mammal in which it is desirable toimprove the supply of nutrients during strenuous exercise. Subjectsinclude, for instance, humans, horses, and dogs.

The patch may be a transdermal patch, a sublingual patch or buccalpatch. Preferably, it is a transdermal patch. In general, transdermalpatches include an athletic supplement reservoir, which may optionallyinclude a permeation enhancer and/or a matrix, an impermeable backinglayer, on one side of the athletic supplement reservoir and an adhesiveoverlay which forms a boundary on the other side of the athleticsupplement reservoir.

Transdermal patches have been described extensively in the art. Forexample, such devices include, but are not limited to, those describedin U.S. Pat. Nos. 3,170,795; 3,598,122; 3,598,123; 3,731,683; 3,742,951;3,814,097; 3,921,636; 3,972,995; 3,993,072; 3,993,073; 3,996,934;4,031,894; 4,060,084; 4,069,307; 4,077,407; 4,201,211; 4,230,105;4,286,592; 4,292,299; 4,292,303; 4,314,557; 4,379,454; and 4,568,343,each of which is hereby incorporated by reference in its entirety.

The term “transdermal delivery” as used herein refers to the transportof compounds across the epidermis, where the compound is absorbed in theblood capillaries. In particular transdermal delivery refers to theadministration of an athletic supplement in a vehicle such as a liquidor solid filler, diluent, excipient, or solvent which is involved incarrying or transporting the athletic supplement across the skin intothe body. A transdermal patch is a skin patch which includes theathletic supplement and which may be applied to the skin of the subject.Many types of materials and designs for the transdermal drug deliveryhave been extensively described, see e.g., D. Hsien, “MultipleLamination for Transdermal Patches,” Controlled Released SystemsFabrication Technology, v. 1, pp. 167-188 (1988).

In a preferred embodiment of the invention, the athletic supplement istransferred by diffusion, preferably in the presence of permeationenhancers. In other embodiments, the athletic supplement may betransferred from the transdermal patch by iontophoresis orelectroosmosis. Iontophoresis is based on the transport of charged ionsby coulombic attraction/repulsion in an electric field. In general,iontophoresis induces an increased migration of ions or chargedmolecules in an electrolyte medium in the presence of the flow ofelectric current. Many transdermal patches which utilize iontophoresisfor transport of drugs have been described such as, for example, U.S.Pat. No. 5,527,797. Electroosmosis is based on the transport of solventin an electric field. Electroosmotic delivery of proteins fromtransdermal devices is described in, for example, U.S. Pat. No.4,940,456.

Preferably the transdermal patch is a passive diffusion patch. A“passive diffusion patch” as used herein is a transdermal patch which isarranged to deliver the athletic supplement across the skin by passivediffusion rather than utilizing an electric field. Preferably itincludes an adhesive layer, a backing layer, and an athletic supplementmatrix layer.

When the patch is a transdermal patch, it is applied to the surface ofthe skin preferably by a contact adhesive layer. The adhesive layer isone which is compatible with the drug and thus does not interact withit. Such materials are well-known in the art and are disclosed in manyof the patents described above which are incorporated by reference.

An adhesive layer prevents excessive migration of the athleticsupplement from the transdermal patch during storage. It allows,however, the athletic supplement to be released into the skin once thepatch is applied. The adhesive layer should also stick securely to theskin once it is applied and also be removed with minimum discomfort.

In order to enhance the ability of the adhesive layer to attach to theskin, it may optionally contain a tackifier. Preferably, the tackifieris a polymer which is insoluble in water and composed of a monomer whichcontains partly or wholly a (meth)acrylic alkyl ester. Such types ofpolymers include, but are not limited to, acrylic, N-butyl-methacryliccopolymer (Primal N580NF, sold by Japan Acrylic Chemical Company, Ltd.),acrylic methyl, acrylic 2-ethylhexyl copolymer (Nikasol TS-6520, sold byNippon Carbide Industries Company, Ltd.), polyacrylic acid (JurymerAC-10LPH, sold by Nihon Junyaku Company, Ltd.), methacrylic copolymer L(Plastoid L50, sold by Rohm Pharma GmbH), and aminoalkylmethacrylatecopolymer E (Plastoid E35L, Plastoid E35M, Plastoid E35H, all sold byRohm Pharma GmbH).

Adhesives useful for applying transdermal patches to the skin of thesubject can be prepared from many types of materials, such aspolyacrylate, silicone, polyisobutylene, and styrene-butadienecopolymers. These types of materials, as well as others, are describedin “The Handbook of Pressure Sensitive Adhesive Technology,” SecondEdition (1989), van Norstrand, Reinold, which is hereby incorporated byreference.

In one embodiment, the adhesive material is an acrylic adhesiveincluding at least one polymer selected from homopolymers of acrylicesters, copolymers of two or more types of acrylic ester units andcopolymers of acrylic esters and other functional monomers. Acrylicesters include, but are not limited to, butyl(meth)acrylate,pentyl(meth)acrylate, hexyl(meth)acrylate, heptyl(meth)acrylate,octyl(meth)acrylate, nonyl(meth)acrylate, decyl(meth)acrylate, etc.Functional monomers include, but are not limited to, monomers containinga hydroxyl group, such as hydroxyethyl(meth)acrylate,hydroxypropyl(meth)acrylate, etc. and monomers containing an amide groupsuch as methacrylate, dimetheylmethacrylamide, etc.

Cross-linked acrylate based adhesives (Avery Chemical Division, MillHall, Pa.) are useful in some embodiments such as when aplasticizer-type enhancer is used. Examples of commercially availablematerials include Avery 2533 adhesive, AS-460HPX (both from AveryChemical Division), Duro-Tak® 9852 (National Starch, Bridgewater, N.J.)and Gelva GE 1753 (Monsanto).

Silicone adhesives are one type of adhesive commonly used in transdermaldelivery devices. Silicone adhesives which are useful for forming theadhesive layer include but are not limited to high molecular weightpolydimethyl siloxanes or polydimethyl diphenyl siloxane that containresidual silanol groups on the ends of the polymer chains, such as thosedescribed in U.S. Pat. Nos. 5,232,702 and 4,906,169.

Polyacrylate adhesives can be made by copolymerizing one or moreacrylate monomers or are also available commercially from a variety ofsources.

Polyisobutelane adhesives are mixtures of high molecular weight and lowmolecular weight polyisobutelanes. Such mixtures have been described inthe art, e.g., PCT/US91/02516.

The adhesive layer may be a single continuous layer across the entiresurface of the transdermal patch. Alternatively, it may cover theperimeter edges of the patch but not the area from which the athleticsupplement is released

A membrane separates the athletic supplement from the adhesive layer.This membrane preferably does not limit the flow of athletic supplementfrom the device into the skin. Therefore, the rate of permeation of theathletic supplement through the membrane is greater than through theskin. Microporous membranes which are useful for this purpose includepolyethylene and polypropylene films, nylon, and nitrocellulose films.Many such membranes are commercially available, including Cotran® 9701,Cotran® 9711 (polyethylene membranes, 50 μm in thickness, with a voidvolume of greater than 10%, 3M Corporation, St. Paul, Minn.), CelgardK256 (Hoechst-Celanese, Charlotte, N.C., microporous polyethylene),Solupor® SP.03, and Solupor® 7P2.0 (microporous polyethylene films, poresize 0.1-5.0 microns, DSM Solutech, The Netherlands).

The athletic supplement may be incorporated into a matrix. The use of amatrix construction can allow a high rate of delivery of the athleticsupplement without the need to add additional permeation enhancers.Patents such as U.S. Pat. No. 5,770,219 describe solid matrix systemsfor enhanced transdermal drug delivery. The patent describes matricesmade from acetate-acrylate copolymers which have unexpectedly high ratesof drug delivery. These acetate-acrylate copolymer materials arecommercially available from a variety of sources including MonsantoChemical Company (Gelva®, which is a vinyl acetate-acrylate copolymerresin solution 737, and Gelva® 788), and Morton Thiokol, Inc. (Mortstik207A and Mortstik 607, which are acrylate copolymers).

The matrix material in which the athletic supplement is incorporated maybe any type of material which is compatible with the drug, and may, forexample, be a gel or a polymer. Some materials which are useful includenatural and synthetic rubbers, other polymeric materials, mineral oil,and petroleum jelly.

The matrix may also contain additional materials such as stabilizers,dyes, pigments, fillers, tackifiers, and excipients. Such additionalmaterials are well-known in the art of transdermal delivery devices.Fillers include, for example, inorganic powders, such as precipitatedsilicic acid anhydride; cellulose derivatives, such as sodium celluloseglycolate (sodium carboxymethylcellulose), methylcellulose,hydroxyethylcellulose, hydroxypropylcellulose,hydroxypropylmethylcellulose, and synthetic polymers, such as polyvinylalcohol and polyvinylpyrrolidone; gelatin, gums, and starch.

The backing layer is impermeable and defines the top of the transdermaldelivery patch. The backing is occlusive because it prevents loss of theathletic supplement and/or enhancers to the environment. The backinglayer may be prepared from any material which is impermeable to theathletic supplement and other components of the patch. It may be asingle layer or may be composed of several different types of layers.Many polymers are useful for making backing layers, such aspolyvinylchloride, polyvinylidene chloride, polyolefins, polyethylene,polypropylene, polyurethane, and polyesters. In addition to thesematerials, polyamides, metal vapor deposited films or sheets thereof,rubber sheets, films, expanded synthetic resin sheets, unwoven fabrics,fabrics, knitted fabrics, papers, and foils may also be used. Thematerials may be laminated, pigmented or metalized.

Although backing layers may be prepared directly from raw materials,they may also be obtained as films from commercial sources. Forinstances, 3M Corporation, St. Paul Minn.; Dow Chemicals, Midland,Mich.; Avery Specialty Tape Division, Plainsville, Ohio; and A.F.Packaging, Winston-Salem, N.C., all supply commercially available filmswhich can be used for backing layers. One type of backing layer which iscommercially available from 3M Corporation is the Scotch Pak 1000. Thebacking layer may be made from Scotch Pak® 1006 or 1009, which are skincolored aluminized polyester films of 50 μm in thickness. Another typeof backing layer is 3M-1012 which is a transparent polyester filmlaminate. Each of these commercially available backing layers is sold by3M Corporation.

Transdermal patches can be formulated so as to produce an occlusive areawhich traps sweat between the skin layer and the patch causing hydrationof the skin which will facilitate movement of the athletic supplementacross the skin Patches which function in such a manner are described inU.S. Pat. No. 5,466,465.

Generally the transdermal patch includes a liner which is positionedadjacent to the surface of the adhesive layer and which is removed priorto application of the transdermal patch to the skin The liner which isused to cover the adhesive backing during storage and to prevent avaporative loss of the athletic supplement during storage may be madefrom any impermeable film. It may be made from the same material as thebacking layer or it may also be a metal foil, Mylar® polyethyleneterphthalate, siliconized polyester, fumed silica in silicone rubber,polytretrafluoroethylene, cellophane, siliconized paper, aluminizedpaper, polyvinyl chloride film, etc.

The patches are generally stored in pouches which will preventcontamination and prevent damage associated with environmentalconditions such as light and dryness. Foil pouches are particularlyuseful. Many types of storage pouches are commercially available, suchas those available from Lithotype Company (San Francisco, Calif.;polyethylene, surlyn), James River Corporation (San Leandro, Calif.;polypropylene metalized film), Ivers-Lee, a division of Becton-Dickinson(West Caldwell, N.J.; 305W, 406), Jefferson Smurfet (Alton, Ill.;acrylonitrile butadiene copolymer film laminate).

In addition to the standard layered polymeric patches described above,the patch of the invention may also be a hydrogel matrix patch. Hydrogelmatrix patches in general include alcohol, water, reactive agent, andhydrophilic polymers. This matrix may be incorporated into thetransdermal patch between the backing and the adhesive layer.Additionally, the layer may be a liquid reservoir instead of a matrix.

In order to increase the skin permeability of the athletic supplementwhich is administered by transdermal devices, the skin may be treatedwith various chemicals prior to administration of the transdermaldevice, or compounds such as permeation enhancers may be deliveredconcurrently with the athletic supplement through the device.

“Permeation enhancers” as used herein increase the permeability of skinto a poorly skin permeating active agent. Many types of permeationenhancers have been described in the prior art. For instance, U.S. Pat.Nos. 4,299,826; 4,343,798; 4,046,886; 4,130,643; 4,405,616; 4,335,115;4,130,667; 3,903,256; 4,379,454; 3,527,864; 3,952,099; 3,896,238;3,472,931; 4,637,930; 4,788,062; 4,746,515; 4,863,738; 4,863,970;5,053,227; 5,613,958; 5,641,504; 5,693,335; and 5,641,504, as well asGreat Britain Patent Nos. 1,011,949 and 2,142,238A and Idson et al.,“Percutaneous Absorption,” J. Pharm. Sci. (1975), 64, pp. 901-924 alldescribe various types of permeation enhancers. The patch of theinvention may include one or more permeation enhancers.

In particular, U.S. Pat. No. 5,641,504 describes a compound, glycerolmonolineate (GMLO) which is effective in enhancing the permeation ofcompounds through body surfaces and in particular through the skin. GMLOenhances the permeability of compounds to allow them to be delivered attherapeutically effective rates with reasonably sized transdermaldevices. The GMLO is coadministered with a compound such as a drug tothe body surface through a transdermal device.

Various types of permeation enhancers are useful according to theinvention. For instance, polar solvents, such as dimethylsulfoxide,decylmethylsulfoxide, dimethylformamide and dimethylacetamide;cycloalkanes, such as azacycloheptan-2-one and1-dodecylazacyloheptan-2-one; esters of carboxylic acids and alcohols,such as isopropyl, myristate and isopropyl palmitate; glycols; surfaceactive agents, such as sodium laurylsulfate and sodium dodecylsulfate;derivatives of fatty acids, pyroglutamic acid and urea; and derivativesof amino acids having the formula R¹NH—R³—COOR² wherein R¹ is a hydrogenatom, an acyl group having 1-20 carbon atoms or a hydrocarbon grouphaving 1-20 carbon atoms, R² is a hydrogen atom or a hydrocarbon grouphaving 1-20 carbon atoms, and R³ is CH—R⁴ or phenyl, wherein R⁴ is H,CH3, isopropyl group, 2-methylpropyl group or 1-methylpropyl group.Amino acid derivatives are described in U.S. Pat. No. 5,413,794 and area preferred type of permeation enhancer. Ethanol has been found toincrease the solubility of drugs up to 10,000-fold and to yield agreater than 100-fold flux increase in drugs and thus also a preferredpermeation enhancer.

Permeation enhancers may be plasticizer-type enhancers or solvent-typeenhancers. Both types of enhancers can be used together. Aplasticizer-type enhancer generally is a fatty acid or fatty alcoholthat is capable of increasing the permeability of a compound to thestratum corneum. The plasticizer-type enhancers migrate into the stratumcorneum layers of the skin and enhance migration of the compounds withinthe transdermal patch into the skin by increasing the mobility and/orsolubility of the compound within the skin Solvent-type enhancers arehydrophilic compounds having molecular weights of about 200 or lesswhich increase the permeability of drugs to the stratum corneum. Thesetypes of enhancers produce high flux rates of the compound within thetransdermal device. When plasticizer enhancers and solvent-typeenhancers are used together, a synergistic effect is achieved whichresults in a high delivery rate of compound across the skin barrier.Many types of plasticizer enhancers and solvent-type enhancers aredescribed in detail in U.S. Pat. No. 5,613,958, which is herebyincorporated by reference.

Some plasticizer type permeation enhancers such as unsaturated fattyacids function by disrupting the lipid bilayer causing an increase inthe solubility of lipid bilayers. Fatty acids, which are useful aspermeation enhancers, and which disrupt lipid bilayers, include linoleicacid, capric acid, lauric acid and neodecanoic acid. The permeabilityenhancement of permeation enhancers for each compound to be transportedcan be calculated according to ε_(e/pg)=P^(e/pg)/P^(pg′). P^(e/pg) isthe drug permeability from the enhancer/propylene glycol formulation andP^(pg) is the permeability from propylene glycol alone. A morecomprehensive list of lipid bilayer disrupting agents is described inEuropean Patent Application No. 043,738 (1982).

Many patents have described permeation enhancers which are solubilityenhancers. These patents include, for instance, U.S. Pat. Nos.4,537,776; 4,973,468; 4,820,720; 4,863,970; and 5,006,342, as well asGreat Britain Patent Application No. 2,153,223A and European PatentApplication No. 043,738.

In addition to the permeation enhancers described above, U.S. Pat. No.4,865,848 describes a novel type permeation enhancer which is sucrosemonolaurate. This sucrose ester can be dispersed within the matrix alongwith the active agent.

Various preservatives may also be used to stabilize the athleticsupplements contained within the transdermal patch. The type ofpreservative selected will depend on the type of components used withinthe athletic supplement as well as the matrix and other materials of thepatch. Preservatives include, but are not limited to, alcohols, e.g.,ethanol or isopropanol; quatrinary ammonium surfactants, as well as manyother preservative compounds known in the art. The United StatesPharmacopeia XXI 1985 includes a section which describes parameters forselecting compounds useful in enhancing the stability of various drugs(pp. 1345-1347). Other factors, such as pH and ionic strength of thesolution, also influence the stability of the compounds within theathletic supplement.

Another preferred dosage form is a sublingual tablet. Preferably, thesublingual tablet disintegrates and releases the athletic supplement tothe sublingual mucosa within a ten minute period of time and mostpreferably within five minutes.

The patch of the invention is designed to deliver the athleticsupplement for an extended period of time of a week or longer.Preferably, the athletic supplement is released within a period of 24hours or less. It is desirable to have the athletic supplement bereleased during the period of the athletic event and any recoveryperiod. Patches may be designed which release the athletic supplementfor various periods of time, such as 12 hours, 8 hours, 6 hours, 4hours, or 2 hours. The type of patch used will depend upon theparticular athletic event and other parameters, such as whethernutrients are obtained through other means.

In some embodiments, it is desirable to apply the patch before or at thestart of the athletic event. If the patch is the primary source ofathletic supplement during the event, then preferably the patch willinclude at least one carbohydrate, chromium, and an energy enhancer. Ifan additional athletic supplement is being administered, such as asports drink, the patch will preferably include a mixture of componentsthat are not found within the sports drink or for which it is desirableto administer a higher quantity of the nutrient. In other embodiments,it is desirable to apply the patch during the course of the athleticevent. For instance, when an additional athletic supplement, such as asports drink or sports bar is administered prior to the athletic event,then it may be desirable to apply the patch at a later time period tosupplement the nutrients that are being lost. At any point, the patchmay be used in combination with sports drinks or sports bars or othertypes of athletic supplements. In another embodiment, the patch may beapplied near the end of the exercise or after the excercise has beencompleted. It may be desirable to do this to prevent cellular damagecaused by a loss of nutrients. For instance, it has been demonstratedthat there is an increase in leucine oxidation during exercise whichresults in an increased net protein breakdown. The administration ofamino acids through the patch after exercise helps to increase proteinsynthesis and prevent breakdown to result in a net improvement in muscleprotein balance. Thus it is particularly preferred that a patch which isto be used after exercise is complete includes amino acids.

The rate of release of the athletic supplement and any permeationenhancers from a passive diffusion patch may be controlled in a varietyof means. For instance, the matrix material in which the athleticsupplement is incorporated may be manipulated to control the speed withwhich the athletic supplement is released. Additionally, the transdermaldelivery device may include a rate controlling membrane which controlsthe release rate further. Rate controlling membranes may be preparedfrom permeable, semipermeable, or microporous materials. Such materialsare well-known in the art for controlling the delivery of drugs. Thematerials may be prepared from, for example, polyethylene, polyvinylacetate, and ethylene vinyl acetate copolymers.

U.S. Pat. No. 5,656,286, which is hereby incorporated by reference inits entirety, describes an improved pressure sensitive adhesivecomposition which is suitable as a matrix for controlled release of adrug and which is composed of a blend of a rubber based pressuresensitive adhesive and a soluble polyvinylpyrrolidone (PVP). A pressuresensitive adhesive is a viscoelastic material which adheres tosubstrates with only slight pressure and remains tacky. It was describedin the patent that the transdermal permeation rate of a compound couldbe controlled by selectively modulating the solubility of the compound.The transdermal permeation rate means the rate of passage of the drugthrough the skin. The solubility parameter is the sum of all theintermolecular attractive forces which are related to the mutualsolubility of the compounds. Many methods are known for determiningsolubility parameters. The permeation rate is controlled by altering thedifferences in the solubility parameters of the adhesive material versusthat of the compounds within the athletic supplement. Thesemanipulations are well-known in the art and in particular described inU.S. Pat. No. 5,656,286.

U.S. Pat. No. 5,466,465 describes the use of a visible indicator forwhich changes in color indicate the status of the athletic supplementwithin the patch. For instance, the indicator may display one color whenthe patch contains a significant amount of athletic supplement, but asthe amount is depleted, the color changes to indicate that depletion.The use of the visual indicator can be of help to the subject todetermine whether it is necessary to apply an additional patch duringthe athletic event. The entire contents of U.S. Pat. No. 5,466,465 areincorporated herein by reference.

The transdermal patch may be of any shape, such as oblong, square,round, rectangular, etc. The transdermal patch may also have a varietyof sizes. The total surface area in general may range from 1-400 cm².The actual surface area will depend upon a number of factors, includingthe amount of athletic supplement to be delivered over a specifiedperiod of time, and the presence or absence of permeation enhancers aswell as the type of adhesive layer and membrane material. When patchesare greater than 100 cm², it is preferred that the adhesive layer doesnot cover the entire surface of the patch, to reduce irritation of theskin In some cases, it is preferred to use textile fabrics for largerpatches.

U.S. Pat. No. 5,473,966 describes a method for sizing transdermalpatches. The method is useful for reducing the size of the patch, andthus the amount of active ingredient within the patch which will beadministered. The method can be used to customize patches for releaseprofiles of the athletic supplement over specific periods of time. Forinstance, if a subject were using a 50 cm² patch and desired to use onethird less athletic supplement, it would be possible to reduce the patcharea to 33 cm² following such a method, or using any such method knownin the art.

The transdermal patch may be a standard single compartment patch or insome embodiments it may be a multi-compartmentalized patch, such asthose described in U.S. Pat. No. 4,666,441. Multi-compartmentalizedpatches are useful, for example, for differentially regulating thecomponents within the athletic supplement and how they are administered.For instance, it may be desirable to consistently administer acarbohydrate throughout the entire athletic event, but to onlyadminister electrolytes and vitamins during later periods, once thesupply of these nutrients has become depleted. This can be accomplishedby including the carbohydrate within one compartment of the transdermalpatch within a matrix which will allow for the continuous administrationover the entire time period and by incorporating the other componentswithin a different compartment which is designed to release thecomponents after a specified time period. Means for controlling the timefor release of components from transdermal patches is well-known in theart, and may be accomplished, for instance, by including an additionallayer of matrix which must be dissolved first before the athleticsupplement can begin to permeate across the skin.

The patch of the invention provides all of the nutritional,carbohydrate, and energy requirements of an athlete under conditions ofphysical stress without causing gastrointestinal disturbances. Ingeneral, athletes experience athletic stress when their metabolic rateexceeds approximately 500 kcal per hour as a result of physicalexertion, or, alternatively, when through sustained exertion a pulserate of 125 beats per minute or higher is maintained for a period of 90minutes or more. Under such conditions, supplemental nutrient sourcesare required. Additionally, under conditions of physical exertion thereis an increased use of amino acids from muscle tissue as an energysource, and an increased percentage of total calories are supplied bythe direct oxidation of the branched chain amino acids, leucine,isoleucine, and valine. (K. G. Schott, et al., “On the Role ofBranched-Chain Amino Acid in Protein Metabolism of Skeletal Muscle,”Journal of Z Naturforsch, May-June 1985, pp. 427-437; S. F. Lowry, etal., “Influence of Nutritional Status on Exertion Induced Four Arm AminoAcid Metabolism in Normal Man,” Journal of Surgical Research, May 1984,Vol. 36, pp. 438-445, and A. E. Harper, et al., “Branched-Chain AminoAcid Metabolism,” Annual Review of Nutrition, 1984, Vol. 4, pp.409-454). The breakdown of muscle protein during such conditions can beassessed by the presence of nitrogen in urine. If branched chain aminoacids are administered during exercise, loss of nitrogen is notdetected.

The ability of a patch of the invention to counteract the physiologicaleffects of physical exertion such as the breakdown of muscle protein orloss of other important nutrients can be assessed in several ways. Forinstance, the effect of the patch may be assessed by using conventionalexperimental parameters to measure the percent of the components whichenter the bloodstream and which are present during the prescribed timeperiod, such as during the athletic event. Quantitative analysis can beassessed by isolating blood samples at various time points after thepatch has been applied and measuring the amount of nutrients in theblood. A normal range of parameters includes serum bicarbonate (24-26mEq/L), serum potassium (3.5-5.3 mEq/L), serum chloride (96-106 mEq/L),serum uric acid (3-9 mg/dl), serum phosphorus (2.5-4.5 mg/dl), andlactate (0.1.6 mEq/L), sodium (135-147 mEq/L), urine pH (5.1-9.0). An invitro quantitative assay is provided in the Examples below. This assayis useful for assessing the appropriate amounts of nutrients whichshould be included in a particular patch.

Alternatively the effect of the patch can be assessed using qualitativemeasures reported by the subject wearing the patch. That is, the patientmay decide whether the patch has beneficial effects during the period ofexertion. These types of qualitative assessment tests have been usedsuccessfully to evaluate many types of treatments for chronic illnessesas well as addictions. The simplest form of qualitative analysisinvolves the use of a nutrient patch for some experimental subjects andplacebos for others. Each subject determines whether the treatmentimproved, worsened or made no change in their ability to withstandstrenuous exercise.

The amount of athletic supplement present in the patch depends onseveral factors, such as the desired time frame for release of theathletic supplement, the anticipated intensity of the athletic event,the particular components within the athletic supplement, thepermeability of the matrix and adhesive layer. In a preferredembodiment, the athletic supplement is present in the matrix atapproximately 0.01-20% athletic supplement, 50-90% matrix, i.e.,polymer, and 1-70% permeation enhancer. In some cases, a secondarypermeation enhancer may also be included.

Examples Example 1 Preparation of a Transdermal Patch

Many techniques are well-known in the art for preparing transdermalpatches from each of the above-described components. One method referredto as the form-fill-seal technology is performed using layeringtechniques. The adhesive is layered onto the liner, and then themembrane material if present is affixed to the adhesive. The athleticsupplement is incorporated into a reservoir and dispersed either on thebacking or the membrane, and then the backing is sealed to the membrane.Many other methods are well known in the art. The patches of theinvention can be prepared by any such method.

The athletic supplement is mixed and in some cases sonicated with orwithout a skin permeation enhancer. For instance, a mixture of freeamino acids may be dry blended to produce a fine amorphous uniformpowder, which generally should be accomplished at around 40° C. andusing blending. The mixture should be blended for at least 1 minute andpreferably between 2 and 5 minutes. The blending may be accomplishedusing a powder mill, such as a Waring Model No. 34BL22 blender. Asuitable copolymer resin, such as Monsanto GELVA® 737 vinyl acetateacrylate copolymer resin adhesive solution is then added to the athleticsupplement mixture and rotated for an extended period of time. Theathletic supplement mixture is then cast on a polyester film to about100 micrometers in thickness. The solvent in the polymer system isevaporated under high temperature such as 75° C. in a forced air oven.The resultant athletic supplement reservoir matrix is then laminatedwith a backing layer film.

Example 2 Single and Multi-Compartmentalized Patches

An example of a transdermal patch of the invention is shown in FIG. 1.The patch of FIG. 1 includes a diffusion matrix layer that uses areticulated macroporous polymeric foam as a framework for holding aviscoelastic athletic supplement-polymer mixture. The patch, 10, is afour-layer, laminated composite that is adapted to be adhered to theskin The outermost layer, the backing layer, 12, functions as theprimary structural element of the device and also serves as a protectivecovering to prevent the athletic supplement from being transmitted fromthe device via the outermost surface. The backing layer, 12, preferablyis made from a sheet or film of a resilient elastomer, such as thosedescribed above, of about 10-75 microns in thickness.

The athletic supplement-containing matrix layer, 14, functions as areservoir for the athletic supplement, a permeation enhancer, andoptionally a pressure sensitive adhesive. The framework of the matrix isa reticulated macroporous polymeric foam, 16. Preferably, the network isessentially completely open pores (90% or greater). The pore rating ofthe reticulated foam will normally be in the range of about 10-40 poresper linear centimeter and the density (unfilled) will typically be inthe range of about 0.01-0.5 g/cm³. As described in more detail above,the polymer is useful for such foam frameworks may be manufactured frompolyurethanes and polyethylenes.

A pressure sensitive adhesive layer, 18, covers the exposed face of thematrix layer, 14. A release liner, 20, covers the other side of thepressure sensitive adhesive. The pressure sensitive adhesive layer, 14,is generally a medical grade adhesive composition having a thickness onthe average of 25-100 microns. Useful materials for forming the adhesiveare described above, and include for instance polydimethylsiloxane.

The pores of the foam may be wholly or partially filled with aviscoelastic hydrophobic athletic supplement-permeable polymer and anenhancer. The polymer, as described above, acts as a carrier for theathletic supplement. The enhancer functions to control the solubility ofthe athletic supplement in the polymer and/or absorption into the skin.The hydrophobic polymer renders the device water resistant and preventsliquid water from being absorbed by the device, thereby increasing itsfunctionality and wearability.

A multicompartmentalized patch is shown in FIG. 2. The patch of FIG. 2also is a four-layer composite but defines at least two separatecompartments for containing the components of the athletic supplement.One compartment contains, for instance, some of the components such asthe carbohydrate, and the other compartment contains other componentssuch as vitamins and electrolytes. The patch, 22, has a backing layer,24, sealed to a rate controlling membrane, 26, in a manner to create twochambers, the first athletic supplement containing chamber, 28, and thesecond athletic supplement containing chamber, 30. An adhesive layer,32, covers the rate controlling membrane and a release liner, 34, coversthe adhesive layer.

The mutlicompartmentalized patch may be prepared by the followingmethod. A silanized polyester (or other suitable material, describedabove) approximately 75 microns thick is used as release sheet, 34. Theadhesive layer, 32, is cast onto the release sheet, and may be forexample polyisobutylene. The adhesive layer is then laminated to therate controlling membrane, 26, which may be about 100 microns thick.Next, the materials which will become the contents of the athleticsupplement containing chambers 1, 28, and 2, 30, are placed in separateareas on the rate controlling membrane, 26. Finally, a suitable backinglayer, 24, having a heat sealable coating on one surface is placed overthe two areas which are to become chambers 28 and 30, and the device isheat sealed, 36, around the parameter and between the two areas to formthe two chambers, 28, and 30.

Referring to FIG. 1 which illustrates an exemplary transdermal patch ofthe invention, the backing sheet 10 is a lightweight pliable strip whichcovers an entire surface of the transdermal patch. The backing sheet 10covers the active agent reservoir 12 on one surface. On the othersurface of the reservoir, the adhesive layer 14 covers the reservoir. Aprotective undercoating 16 is positioned adjacent to the adhesive layer.The protective undercoating is removed prior to contacting the adhesivelayer with the skin

Example 3 Quantitative Assay of Release of Nutrients from a TransdermalPatch

A modified Franz flow-through cell system can be used for in vitropenetration studies to determine the efficiency of the particular matrixat delivering the athletic supplement. One of the polyester layers ispeeled off of the athletic supplement matrix layer. The athleticsupplement matrix layer is then pressed onto the stratum corneum ofhuman cadaver skin membrane. This skin membrane with the backing andmatrix affixed thereto is then mounted between two half cells andfastened with a clamp. The receiver compartment is filled with 0.1%gentamycin in distilled, deionized water, and the temperature ismaintained at 32° C. Samples are taken at preset intervals and assayedby HPLC or other known assays. The type of assay depends on thecomponent within the athletic supplement to be identified. The flux isthen calculated from the slope of the cumulative amounts of the athleticsupplement in the receiver compartment versus time.

Example 4 Preparation of a Sublingual Tablet

One method for preparing sublingual tablets is described below. In theexample sublingual tablets are made in accordance with the formulationset forth in Table 1 and Table 2 below.

TABLE 1 Branched chain amino acids  10 mg Mannitol, USP (DC grade) 31.5mg  Microcrystalline, Cellulose 40.35 mg  Sodium Starch Glycolate NF 2.6mg Sodium Saccharin, USP 0.5 mg Flavor S.D. Peppermint, FCC 0.75 mg Magnasweet MM 188M 0.5 mg Vanilla flavor #800 0.2 mg D&C Yellow #10,Aluminum Lake 0.2 mg Magnesium stearate, NF 0.5 mg Aerosil 200 0.4 mgTOTAL  80 mg

TABLE 2 Branched chain amino acids   5 mg Vitamin C   5 mg b-carotene0.20 mg Choline 0.02 mg Octacosanol 0.02 mg Vitamin B 0.50 mg Mannitol30.30 mg  Microcrystalline cellulose (FMC) 4.00 34.00 mg  Sodium starchglycolate (EXPLS TAB Mendell) 2.60 mg Magnesium stearate NF 0.50 mgColloidal silicon dioxide (Aerosil 200) 0.40 mg Sodium saccharin(Mallinckrodt) 2.00 mg Aspartame (Neutrasweet) 4.00 mg Peppermint(Virginia Dare HF82 SD #517) 0.40 mg Vanilla (Virginia DAre 800 NAT)0.30 mg MAFCO Magnasweet 188M 0.25 mg Prosweet #560 (MM54) 0.75 mgChocolate Flavor #682 2.00 mg D&C Yellow #10   0 mg TOTAL (mg) 85.00 mg 

The formulations set forth in Tables 1 & 2 represent examples ofsublingual tablet formulations. Individuals skilled in the art willrecognize that modifications to the formulation can be readily made.

In the above formulation, mannitol, sodium saccharin, peppermint,magnasweet, vanilla, aspartame, prosweet, and chocolate are flavoringagents which are capable of masking the bitter taste of some of thenutrients such as the branched amino acids. The flavoring agents may bedeleted without sacrificing efficacy. However, the sublingual tablet mayhave an unappealing taste. Flavorings may be altered to suit individualneeds and tastes.

D&C yellow is used as a colorant. The colorant may be readily deleted orsubstituted with other dyes.

Magnesium stearate and Aerosil-200 are lubricants to release the tabletfrom press equipment. These ingredients may be substituted or deletedentirely depending on the manufacturing process.

Microcrystalline cellulose, mannitol and sodium starch glycolate providethe tablet core. The cellulose and starch facilitate binding the coreingredients and facilitate tablet disintegration in the presence ofmoisture. The relative amounts of these ingredients may be altered toadjust the disintegration of the tablet.

Quantities of all ingredients are weighed and all the ingredients, otherthan mannitol, are passed through a 80 mesh stainless steel sieve. Thematerials are blended in a suitably sized polythene bag for about fiveminutes and transferred to suitable blender, such as a PK Blender. Therequired quantities of mannitol are passed through a 40 mesh stainlesssteel sieve and added to the PK Blender with the other ingredients. Themixture is blended in the PK Blender for 10 minutes and unloaded. Asample of the blend is subjected to inspection for potency and otherquality determining criteria. The bulk density is determined on theblend using bulk density apparatus set for 100 taps. The tablet press isset for the designated punches and the blend is compressed at 80 mgtablet weight.

The sublingual tablets are administered by placing a tablet under thetongue. The tablet is allowed to disintegrate and release the athleticsupplement which is absorbed by the sublingual mucosa.

Example 5 Qualitative Analysis of a Patch

An assay for qualitative analysis of a combination of transdermalpatches and sublingual tablets of varying strength is described.Sublingual tablets and transdermal patches are prepared in accordancewith Examples 1 and 4. A placebo sublingual tablet and transdermal patchare formed by incorporating an inert material. These tablets and patchesare administered to subjects just prior to or during strenuous exercise.A preferred method is to apply a transdermal patch to a subject prior tothe start of the exercise and to administer a sublingual tablet duringthe exercise after the depletion of nutrients has begun.

The subjects are asked to evaluate various parameters of their wellbeing throughout the course of the exercise. For instance, each subjectassesses their general energy level, endurance, athletic performance andfatigue on a numerical 0-4 scale. The results are assessed for eachathlete using various combinations of patches, sublingual tablets, orplacebo under similar exercise conditions on different days.

The foregoing written specification is considered to be sufficient toenable one skilled in the art to practice the invention. The presentinvention is not to be limited in scope by examples provided, since theexamples are intended as a single illustration of one aspect of theinvention and other functionally equivalent embodiments are within thescope of the invention. Various modifications of the invention inaddition to those shown and described herein will become apparent tothose skilled in the art from the foregoing description and fall withinthe scope of the appended claims. The advantages and objects of theinvention are not necessarily encompassed by each embodiment of theinvention.

All references, patents and patent publications that are recited in thisapplication are incorporated in their entirety herein by reference.

1. A method of administering nutrients to a subject, the methodcomprising: transdermally administering an athletic supplement, whichconsists essentially of two or more of the following componentscarbohydrate, electrolyte, vitamin, pyruvate, chromium, ammonianeutralizers, amino acid, mineral, and energy enhancer, to the subjectfrom a patch affixed to the subject while the subject is undergoing aphysical activity to provide the subject with nutrition and energy toperform the physical activity, wherein the athletic supplement includesat least one carbohydrate in an effective amount for maintainingcarbohydrate levels in blood within a normal range and at least onecompound selected from the group consisting of an electrolyte, avitamin, an amino acid, a mineral, and an energy enhancer.
 2. The methodof claim 1, wherein the athletic supplement includes an electrolyte. 3.The method of claim 1, wherein the athletic supplement includes avitamin.
 4. The method of claim 1, wherein the athletic supplementincludes an amino acid.
 5. The method of claim 1, wherein the athleticsupplement includes a mineral.
 6. The method of claim 1, wherein theathletic supplement includes an energy enhancer.
 7. The method of claim1, wherein the athletic supplement includes a vitamin, an amino acid, amineral, and an energy enhancer.
 8. The method of claim 1, wherein theathletic supplement includes at least one of the following compounds:sodium chloride, potassium chloride, anhydrous magnesium sulphate,dextrose, sucrose, ascorbic acid, pyridoxine hydrochloride, sodiumcitrate, and citric acid.
 9. The method of claim 1, wherein the patchincludes a matrix and wherein the athletic supplement is incorporatedinto the matrix.
 10. The method of claim 1, wherein the matrix includesa filler.
 11. The method of claim 1, wherein the patch includes apermeation enhancer.